Compositions for the treatment of dry eye

ABSTRACT

The present invention relates to ophthalmic compositions and methods useful to treat dry eye, or to diagnose, cure, mitigate, treat, or prevent dry eye syndrome in man or other animals.

CROSS REFERENCE

This application is a continuation of U.S. patent application Ser. No.16/129,385, filed Sep. 12, 2018, which is a continuation of U.S. patentapplication Ser. No. 14/601,781, filed Jan. 21, 2015, now U.S. Pat. No.10,105,386, issued Oct. 23, 2018, which is a continuation application ofU.S. patent application Ser. No. 13/645,035, filed Oct. 4, 2012, nowU.S. Pat. No. 8,957,048, issued Feb. 17, 2015, which claims priority toU.S. Provisional Patent Application No. 61/544,151, filed Oct. 6, 2011,each of which are incorporated herein by reference in their entireties,and serves as the basis for a priority and/or benefit claim of thepresent application.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to ophthalmic compositions and methodsuseful to treat dry eye, or to diagnose, cure, mitigate, treat, orprevent dry eye syndrome in man or other animals.

2. Background of the Art

Dry eye is a multifactorial disease of the tears and ocular surface thatresults in symptoms of discomfort, visual disturbance, and tears filminstability with potential damage to the ocular surface. The normal tearfilm is a relatively stable, thin film composed of a superficial lipidlayer and an aqueous layer intermixed with a mucus gel layer which ispartially adherent to the corneal and conjunctival surface epithelium.Natural tear film is important for the lubrication and maintenance ofthe refractive surface of the eye. Dry eye syndrome is a complex diseasecharacterized by a dysfunction of one or more components of the tearfilm, leading to the loss of tear film stability, a hyperosmotic shiftin the tear film osmotic balance, and/or an inadequate amount of fluidon the ocular surface. This is characterized by rapid break-up of thetear film and numerous symptoms, including burning/stinging, foreignbody sensation, itching, and photophobia.

The majority of patients with dry eye syndrome are prescribed orrecommended artificial tears. Also recommended are lid compresses andscrubs, and addition of essential fatty acids to the diet.

Dry Eye Syndrome is a common disorder of the normal tear film thatresults from one of the following: decreased tear production, excessivetear evaporation, an abnormality in the production of mucus or lipidsnormally found in the tear layer.

Aqueous (watery) tear deficiency is caused by either poor production ofwatery tears or excessive evaporation of the watery tear layer.

Poor production of tears by the tear glands may be a result of age,hormonal changes, or various autoimmune diseases, such as primarySjogren syndrome, rheumatoid arthritis, or lupus.

Evaporative loss of the watery tear layer is usually a result of aninsufficient overlying lipid layer. Some medications, such asantihistamines, antidepressants, beta-blockers, and oral contraceptives,may decrease tear production. If blinking is decreased or if the eyelidscannot be closed, the eyes may dry out because of tear evaporation.

Reading, watching TV, or performing a task that requires close attentionwith the eyes, may decrease the blinking, allowing excessive evaporationof the tears.

LASIK and other vision correction procedures can cause dry eyes afterthey penetrate the eye's surface and reduce corneal nerve sensitivity.Afterwards the eye fails to sense the need for lubrication andinadequate tear production results. New ophthalmic compositions fortreating eyes and methods of treating dry eyes have been discovered.

SUMMARY OF THE INVENTION

It has now been discovered novel ophthalmic compositions for treatingdry eye syndrome, which may include a combination of a demulcent or filmforming material and a tonicity agent. These compositions may be used totreat dry eye, or to diagnose, cure, mitigate, treat, or prevent dry eyesyndrome in man or other animals. These formulations are sterile,buffered, oil and water emulsion artificial tear products formulated forthe relief of ocular surface irritation and symptoms of dryness.

These compositions are typically ophthalmically acceptable liquids. Anophthalmically acceptable liquid includes a liquid formulated that istolerable to a patient for topical ophthalmic use. Additionally, anophthalmically acceptable liquid could either be packaged for singleuse, or for multiple uses containing a preservative to preventcontamination.

For ophthalmic application, solutions or medicaments may be preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions may be maintained at a comfortable pH with an appropriatebuffer system. The formulations may also contain conventional,pharmaceutically acceptable preservatives, stabilizers and surfactants.

An ophthalmically acceptable liquid may include demulcents or filmforming materials. Examples of demulcents may include, but are notlimited to polymers such as polyvinyl alcohol, povidone, hydroxypropylmethyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethylcellulose, acrylates; surfactants such as polyoxyethylene (20) sorbitanmonooleate and glycerin. The amount of demulcent may vary. In someembodiments, the amount of any demulcent such as those listed above maybe from about 0.1% w/w to about 2% w/w, or from about 0.3% w/w to about0.7% w/w, or from about 0.3% w/w to about 0.5% w/w, or about 0.5% w/w.

An ophthalmically acceptable liquid may include a buffer. The buffer mayvary, and may include any weak conjugate acid-base pair suitable formaintaining a desirable pH range. Examples include, but are not limitedto, acetate buffers, citrate buffers, phosphate buffers, borate buffers,or a combination thereof. Acids or bases may be used to adjust the pH ofthese formulations as needed. The amount of buffer used may vary. Insome embodiments, the buffer may have a concentration in a range ofabout 1 nM to about 100 mM. The pH of a buffered solution may beincreased by the addition of sodium hydroxide or another base, ordecreased by the addition of hydrochloric acid or another acid. In someembodiments, the pH of a composition may be from about 7 to about 7.5,or from about 7.2 to about 7.4, or about 7.3.

An ophthalmically acceptable liquid may include a preservative. Thepreservative may vary, and may include any compound or substancesuitable for preventing microbial contamination in an ophthalmic liquidsubject to multiple uses from the same container. Preservatives that maybe used in the pharmaceutical compositions disclosed herein include, butare not limited to, cationic preservatives such as quaternary ammoniumcompounds including benzalkonium chloride, polyquad, and the like;guanidine-based preservatives including polyhexamethylene biguanide(PHMB), chlorhexidine, and the like; chlorobutanol; mercurypreservatives such as thimerosal, phenylmercuric acetate andphenylmercuric nitrate; and oxidizing preservatives such as stabilizedoxychloro complexes (e.g. Purite®). Purite® is a registered trademark ofAllergan, Inc.

In some embodiments, the amount of preservative in the liquid may befrom about 0.0001% w/w to about 25% w/w, or from about 0.002% w/w toabout 0.05% w/w, or from about 0.005% w/w to about 0.02% w/w, or about0.01% w/w.

An ophthalmically acceptable liquid may include a surfactant. Thesurfactant may vary, and may include any compound that is surface activeor can form micelles. A surfactant may be used for assisting indissolving an excipient or an active agent, dispersing a solid or liquidin a composition, enhancing wetting, modifying drop size, stabilizing anemulsion, or a number of other purposes. Useful surfactants include, butare not limited to, surfactants of the following classes: alcohols;amine oxides; block polymers; carboxylated alcohol or alkylphenolethoxylates; carboxylic acids/fatty acids; ethoxylated alcohols;ethoxylated alkylphenols; ethoxylated arylphenols; ethoxylated fattyacids; ethoxylated fatty esters or oils (animal and vegetable); fattyesters; fatty acid methyl ester ethoxylates; glycerol esters; glycolesters; lanolin-based derivatives; lecithin and lecithin derivatives;lignin and lignin derivatives; methyl esters; monoglycerides andderivatives; polyethylene glycols; polymeric surfactants; propoxylatedand ethoxylated fatty acids, alcohols, or alkyl phenols; protein-basedsurfactants; sarcosine derivatives; sorbitan derivatives; sucrose andglucose esters and derivatives. In some embodiments, the surfactant mayinclude polyethylene glycol (15)-hydroxystearate (CAS Number 70142-34-6,available as Solutol HS 15® from BASF), polyoxyethylene-polyoxypropyleneblock copolymer (CAS No. 9003-11-6, available as Pluronic® F-68 fromBASF), polyoxyethylene 40 stearate (POE40 stearate), polysorbate 80 orpolyoxyethylene (20) sorbitan monooleate (CAS No. 9005-65-6), sorbitanmonostearate (CAS No. 1338-41-6, available as Span™ 60 from CrodaInternational PLC), polyoxyethylenglyceroltriricinoleat 35 (CAS No.61791-12-6, available as Cremophor EL® from BASF). The amount ofsurfactant may vary. In some embodiments, the amount of any surfactantsuch as those listed above may be from about 0.001% w/w to about 5% w/w,or from about 0.1% w/w to about 2 w/w %, or from about 0.3% to about0.7%, or from about 0.3% w/w to about 0.5% w/w, or from about 0.1% w/wto about 1% w/w, or about 0.5% w/w.

An ophthalmically acceptable liquid may include a stabilizer. Examplesof suitable stabilizers include, but are not limited to, polyvinylalcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose, and acrylates such asacrylates/C10-30 alkyl acrylate crosspolymer (e.g. Pemulen™ RTM,Pemulen™ TR-2). Acrylates/C10-30 alkyl acrylate crosspolymer is sold andis known as Pemulen™ TR-2. In some embodiments, the amount of stabilizermay be from about 0.01% to about 1%, or from about 0.1% w/w to about 1%w/w, or about 0.1% w/w.

An ophthalmically acceptable liquid may include a tonicity agent. Thetonicity agent may vary, and may include any compound or substanceuseful for adjusting the tonicity of an ophthalmic liquid. Examplesinclude, but are not limited to, salts, particularly sodium chloride,potassium chloride, mannitol and glycerin, or any other suitableophthalmically acceptable tonicity adjustor. The amount of tonicityagent may vary depending upon whether an isotonic, hypertonic, orhypotonic liquid is desired. In some embodiments, the amount of atonicity agent such as those listed above may be at least from about0.0001% w/w to about 5% w/w, or from about 0.2% to about 5% w/w, or fromabout 0.5% w/w to about 2% w/w, or about 1.0% w/w.

An ophthalmically acceptable liquid may include an antioxidant. Theantioxidant may vary, and may include any compound or substance that isuseful in reducing oxidation of any compound present in anophthalmically acceptable liquid. Examples, not limited to, are: sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole, and butylated hydroxytoluene.

An ophthalmically acceptable liquid may include a chelating agent. Thechelating agent may vary, and may include any compound or substance thatis capable of chelating a metal. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

Compositions may be aqueous solutions or emulsions, or some otheracceptable liquid form. For an emulsion, one or more oils may be used toform the emulsion. Suitable oils include, but are not limited to aniseoil, castor oil, clove oil, cassia oil, cinnamon oil, almond oil, cornoil, arachis oil, cottonseed oil, safflower oil, maize oil, linseed oil,rapeseed oil, soybean oil, olive oil, caraway oil, rosemary oil, peanutoil, peppermint oil, sunflower oil, eucalyptus oil, sesame oil, and thelike. In some embodiments, the amount of oil such as those listed abovemay be from about 0.0001% w/w to about 5% w/w, or from about 0.005% w/wto about 1 w/w %, or from about 0.01% w/w to about 0.2 w/w %, or fromabout 0.05% w/w to about 0.5% w/w, or from about 0.2% w/w to about 5%w/w, or from about 0.5% w/w to about 2% w/w, or from about 0.1 to about0.2%, or about 0.175% w/w, or about 0.075% w/w.

Other excipients may include erytritol, a carnitine, includingL-carnitine (levocarnitine) or R-carnitine. In some embodiments, theamount of erythritol may be from about 0.05% to about 3% w/w, or fromabout 0.1% w/w to about 0.5% w/w, or about 0.25% w/w.

In some embodiments, the amount of levocarnitine may be from about 0.05%to about 3% w/w, or from about 0.1% w/w to about 0.5% w/w or about 0.25%w/w. Table 1 includes a list of components that may be used in a dry eyecomposition.

TABLE 1 Ingredient Amount Polyoxyethylene (20) omitted, or about 0.1-2%,about 0.3%- sorbitan monooleate 0.7%, or about 0.5% w/wCarboxymethylcellulose omitted, or about 0.1-2%, about 0.3%- sodium (lowviscosity) 0.7%, or about 0.5% w/w Glycerin omitted, or about 0.2-5%,about 0.5-2%, or about 1.0% w/w Purite ® omitted, or about 0.002%-0.05%,about 0.005%-0.02%, or about 0.01% w/w Boric Acid omitted, or about0.02-2%, about 0.5- 0.7%, or about 0.6% w/w A C10-30 alkyl acrylateomitted, or about 0.02-0.5%, about crosspolymer 0.05-0.2%, or about 0.1%w/w Castor Oil omitted, or about 0.05-0.5%, about 0.1- 0.2%, or about0.175% w/w Olive Oil, Super Refined omitted, or about 0.005-1%, about0.01- (non-preserved) 0.2%, or about 0.075% w/w Erythritol omitted, orabout 0.05-3%, about 0.1- 0.5%, or about 0.25% w/w Levocarnitineomitted, or about 0.05-3%, about 0.1- 0.5%, or about 0.25% w/w Sodiumhydroxide omitted, or add to pH of about 7-7.5, 7.2-7.4, or about 7.3.Water QS 100% w/w

DETAILED DESCRIPTION OF THE INVENTION

Some embodiments of the invention comprise, or consist of,Polyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose sodium(low viscosity), glycerin, Purite®, boric acid, an acrylates/C10-30alkyl acrylate crosspolymer (Pemulen™ TR-2), castor oil, olive oil,erythritol, levocarnitine, sodium hydroxide, and water.

Some embodiments of the invention comprise, or consist of,Polyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose sodium(low viscosity), glycerin, Purite®, boric acid, an acrylates/C10-30alkyl acrylate crosspolymer (Pemulen™ TR-2), castor oil, erythritol,levocarnitine, sodium hydroxide, and water.

Some embodiments of the invention comprise, or consist of,Polyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose sodium(low viscosity), glycerin, boric acid, an acrylates/C10-30 alkylacrylate crosspolymer (Pemulen™ TR-2), castor oil, erythritol,levocarnitine, sodium hydroxide, and water.

Some embodiments of the invention comprise, or consist ofpolyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose sodium,glycerin, boric acid, acrylates/C10-30 alkyl acrylate crosspolymer,castor oil, erythritol, levocarnitine, sodium hydroxide, and water.

Some embodiments of the invention comprise, or consist ofpolyoxyethylene (20) sorbitan monooleate, carboxymethylcellulose sodium,glycerin, boric acid, acrylates/C10-30 alkyl acrylate crosspolymer,stabilized oxychloro complexes, castor oil, erythritol, levocarnitine,sodium hydroxide, and water.

EXAMPLE 1

A formulation is prepared for use as an artificial tears productaccording to Table 2:

TABLE 2 Ingredient Amount Polysorbate 80 0.5% w/w Carboxymethylcellulosesodium (low 0.5% w/w viscosity) Glycerin 1.0% w/w Purite ® 0.01% w/wBoric Acid 0.6% w/w Pemulen ™ TR-2 0.1% w/w Castor Oil 0.175% w/w OliveOil, Super Refined (non-preserved) 0.075% w/w Erythritol 0.25% w/wLevocarnitine 0.25% w/w Sodium hydroxide Add to pH 7.3 Water QS 100% w/wThe formulation of Table 2 is administered to a person suffering fromdry eye syndrome about 1-10 times per day for relief of dry eyesymptoms.

EXAMPLE 2

A formulation is prepared for use as an artificial tears productaccording to Table 3:

TABLE 3 Ingredient Amount Polysorbate 80 0.5% w/w Carboxymethylcellulosesodium (low 0.5% w/w viscosity) Glycerin 1.0% w/w Purite ® 0.01% w/wBoric Acid 0.6% w/w Pemulen ™ TR-2 0.1% w/w Castor Oil 0.25% w/wErythritol 0.25% w/w Levocarnitine 0.25% w/w Sodium hydroxide Add to pH7.3 Water QS 100% w/w

The formulation of Table 3 is administered to a person suffering fromdry eye syndrome about 1-10 times per day for relief of dry eyesymptoms.

Some embodiments of the present invention include:

1. An ophthalmic composition comprising polyoxyethylene (20) sorbitanmonooleate, carboxymethylcellulose sodium, glycerin, boric acid,acrylates/C10-30 alkyl acrylate crosspolymer, castor oil, erythritol,levocarnitine, sodium hydroxide, and water.

2. The composition of paragraph 1, wherein the polyoxyethylene (20)sorbitan monooleate is present at a concentration of about 0.1% w/w toabout 2% w/w.

3. The composition of paragraph 1 wherein the carboxymethylcellulosesodium is present at a concentration of about 0.1% w/w to about 2% w/w.

4. The composition of paragraph 1, wherein the glycerin is present at aconcentration of about 0.2% w/w to about 5% w/w.

5. The composition of paragraph 1, wherein the boric acid is present ata concentration of about 0.02% to about 2% w/w.

6. The composition of paragraph 1, wherein the acrylates/C10-30 alkylacrylate crosspolymer is present at a concentration of about 0.02% toabout 0.5% w/w.

7. The composition of paragraph 1, wherein the castor oil is present ata concentration of about 0.05% to about 0.5% w/w.

8. The composition of paragraph 1, wherein the erythritol is present ata concentration of about 0.05% or about 3% w/w.

9. The composition of paragraph 1, wherein the levocarnitine is presentat a concentration of about 0.05% to about 3% w/w.

10. The composition of paragraph 1, wherein the pH is about 7.3.

11. The composition of paragraph 1, comprising about 0.5% w/wpolyoxyethylene (20) sorbitan monooleate, about 0.5% w/wcarboxymethylcellulose sodium, about 1.0% w/w glycerin, about 0.6% w/wboric acid, about 0.1% w/w acrylates/C10-30 alkyl acrylate crosspolymer,about 0.25% w/w castor oil, about 0.25% w/w erythritol, about 0.25% w/wlevocarnitine, sodium hydroxide, a pH of about 7.3 and water.

12. A method of treating, diagnosing, curing, mitigating or preventingdry eye syndrome comprising administering an effective amount of anophthalmic composition according to paragraph 1 to an eye of a man orother animal in need thereof.

13. The method according to paragraph 12, wherein the ophthalmiccomposition comprises about 0.5% w/w polyoxyethylene (20) sorbitanmonooleate, about 0.5% w/w carboxymethylcellulose sodium, about 1.0% w/wglycerin, about 0.6% w/w boric acid, about 0.1% w/w acrylates/C10-30alkyl acrylate crosspolymer, about 0.25% w/w castor oil, about 0.25% w/werythritol, about 0.25% w/w levocarnitine, sodium hydroxide, a pH ofabout 7.3 and water.

14. The composition of paragraph 1, further comprising stabilizedoxychloro complexes.

15. The composition of paragraph 14, wherein the stabilized oxychlorocomplex is present at a concentration of about 0.002% or about 0.05%w/w.

16. The ophthalmic composition of paragraph 11, further comprising about0.01% w/w of stabilized oxychloro complex.

17. A method of treating, diagnosing, curing, mitigating or preventingdry eye syndrome comprising administering an effective amount of anophthalmic composition according to paragraph 14 to an eye of a man orother animal in need thereof.

18. The method according to paragraph 17, wherein the ophthalmiccomposition comprises about 0.5% w/w polyoxyethylene (20) sorbitanmonooleate, about 0.5% w/w carboxymethylcellulose sodium, about 1.0% w/wglycerin, about 0.01% w/w of stabilized oxychloro complexes, about 0.6%w/w boric acid, about 0.1% w/w acrylates/C10-30 alkyl acrylatecrosspolymer, about 0.25% w/w Castor Oil, about 0.25% w/w erythritol,about 0.25% w/w levocarnitine, sodium hydroxide to obtain a pH of about7.3 and water.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained. At the veryleast, and not as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the invention. Of course, variationson these described embodiments will become apparent to those of ordinaryskill in the art upon reading the foregoing description. Accordingly,the claims include all modifications and equivalents of the subjectmatter recited in the claims as permitted by applicable law. Moreover,any combination of the above-described elements in all possiblevariations thereof is contemplated unless otherwise indicated herein orotherwise clearly contradicted by context.

Clinical Aspects:

A completed clinical study had for objective to evaluate the safety,efficacy and acceptability of the two candidates: Formulation A andFormulation B in comparison with Allergan's existing OPTIVE™ Eye dropsin subjects with signs and symptoms of dry eye disease.

The results showed that Formulation A and Formulation B are clinicallysafe and effective in subjects with signs and symptoms of dry eyedisease.

Formulation A is a multidose (MD) formulation containing polysorbate 80,carboxymethylcellulose sodium, glycerin, Purite®, boric acid, Pemulen™TR-2, castor oil, erythritol, levocarnitine, sodium hydroxide, andpurified water for injection, supplied in 15 ml multidose bottles. Thesolution is clinically safe and effective in subjects with signs andsymptoms of dry eye disease.

Formulation B is an unit-dose (UD) formulation containing polysorbate80, carboxymethylcellulose sodium, glycerin, boric acid, Pemulen™ TR-2,castor oil, erythritol, levocarnitine, sodium hydroxide, and purifiedwater for injection, supplied in 0.4 ml unit-dose vials. This solutionis clinically safe and effective in subjects with signs and symptoms ofdry eye disease.

The study was a multicenter, investigator-masked, randomized,active-controlled, 4-arm, parallel group study designed to compare thesafety, efficacy, and acceptability of Formulation A to OPTIVE™Lubricant Eye Drops Multidose (OPTIVE MD) and Formulation B to OPTIVE™Sensitive Preservative-free Lubricant Eye Drops Unit-dose (OPTIVE UD).

Control solution OPTIVE™ Lubricant Eye Drops Multidose (OPTIVE MD)contained carboxymethylcellulose sodium, glycerin, boric acid, sodiumborate, sodium citrate, potassium chloride, levocarnitine, erythrol,calcium chloride, magnesium chloride, Purite®, purified water and sodiumhydroxide to adjust pH to 7.3, supplied in 15 ml multidose bottles.

Control solution OPTIVE™ Sensitive Preservative-free Lubricant Eye DropsUnit-dose (OPTIVE UD) contained carboxymethylcellulose sodium, glycerin,boric acid, sodium borate, sodium citrate, potassium chloride,levocarnitine, erythrol, calcium chloride, magnesium chloride, purifiedwater for injection and sodium hydroxide to adjust pH to 7.3, suppliedin 0.4 ml unit-dose vials.

The duration of the study was 30 days for each subject and consisted ofup to 3 scheduled visits (day 1 [baseline], day 7, and day 30 [exit]).On day 1, eligible subjects with signs and symptoms of dry eye diseasewere assigned according to a 2:2:1:1 treatment allocation ratio to useFormulation A, OPTIVE MD, Formulation B, or OPTIVE UD, respectively.

Approximately 300 subjects were enrolled at 13 to 14 sites within theUSA in order to have 288 completed subjects assuming a dropout rate ofapproximately 5%. For enrollment into the study, each subject had tomeet certain inclusion criteria and none of the exclusion criteria.

Subjects were instructed to instill 1 to 2 drops of their assigned studyproduct in each eye, as needed, but at least 2 times daily for 30 days.Subjects could have voluntarily withdrawn from the study at any time.Additionally, subjects could have been discontinued from the study by aninvestigator for reasons such as adverse events, loss to follow-up,protocol violations, or lack of efficacy.

Subjects randomized to Formulation A, OPTIVE MD received kits containing2 multidose bottles (15 mL in each bottle) of study product, and wereinstructed to use 1 bottle until it was empty and then to use the secondbottle.

Subjects randomized to Formulation B and OPTIVE UD received kitscontaining 180 unit-dose vials (0.4 mL in each vial) of study product,and were instructed to use 1 vial per dosing for both eyes.

Each subject was instructed to instill 1 to 2 drops of study product ineach eye, as needed, but at least 2 times daily for the entire durationof the study (from day 1 after randomization through day 30, prior toexiting the study).

Subjects and all investigative site staff were masked to the studytreatment. To maintain product masking, both the Formulation B and theOPTIVE UD drops were provided in identical 0.4 mL unit-dose vials whilethe Formulation A and the OPTIVE MD drops were provided in identical 15mL multidose bottles.

Primary Efficacy Measurements:

The primary efficacy measure was the Ocular Surface Disease Index®(OSDI) Questionnaire at day 30 in the intent-to-treat (ITT) population.The OSDI Questionnaire consisted of 12 questions with a 5-point scale(0=none of the time; 1=some of the time; 2=half of the time; 3=most ofthe time; 4=all of the time; some questions had a possible “N/A” [notapplicable] response) (Schiffman et al, 2000). Subjects were asked toevaluate the frequency of various symptoms, related visual functions,and environmental triggers of dry eye using the 5-point scale. Subjectswere asked to base their evaluation on the frequency of their symptomsover the last week before the study visit. This was evaluated overall,not per eye.

The primary efficacy analysis was performed on the change from baselinein OSDI score at day 30 via a 2-way analysis of variance (ANOVA) modelwith treatment and baseline OSDI stratification as the main effects.Last observation carried forward (LOCF) was used to impute missing data.Noninferiority was tested using a 2-sided confidence interval (CI). Thetreatment difference and 95% CI in change from baseline in OSDI score atday 30 between Formulation B and OPTIVE UD (Formulation B minus OPTIVEUD) were calculated based on the ANOVA model. Non-inferiority wasestablished if the upper limit of the 95% CI was less than theprespecified margin of 7.3. The primary efficacy endpoint was met. Atday 30, no statistically significant difference was observed between theFormulation B and the OPTIVE UD groups in the mean change from baselinein OSDI score (95% confidence interval [−5.42, 2.51]), in the ITTpopulation. The Formulation B was noninferior to the OPTIVE UDformulation in reducing the severity of symptoms of dryness as measuredby the change from baseline in OSDI score.

Similar to the ITT population, there was no statistically significantdifference between the Formulation B and OPTIVE UD groups of theper-protocol (PP) population in the mean change from baseline in OSDIscore at day 30. The 95% confidence interval at the day 30 visit was(−5.72, 2.37); with an upper limit that is lower than the clinicallyrelevant margin of 7.3.

In all 4 treatment groups, there was a statistically significantdifference (p<0.001) in the mean change from baseline in OSDI score atthe day 7 and day 30 visits for both the ITT and the PP population.

The Formulation B group was noninferior to the Formulation A group inthe mean change from baseline in OSDI score at day 30.

Overall, there were no statistically significant differences between theFormulation B and OPTIVE UD groups, Formulation B and Formulation Agroups, or Formulation A and OPTIVE MD groups.

Efficacy:

The results of this study demonstrate that Formulation B is noninferiorto the OPTIVE UD formulation in reducing the severity of symptoms ofdryness in subjects with mild to severe dry eye.

Safety:

Formulation B appeared to be well tolerated during the study. Throughoutthe study, there were no treatment-related serious adverse events. Thesafety profile was consistent with OPTIVE UD, OPTIVE MD, and FormulationA. This is supportive of the safety of the Formulation B in clinicaluse, and confirms the safety of the Formulation A.

Secondary Efficacy Measurements:

The Secondary efficacy measures included (tear break-up time) TBUT,corneal staining, conjunctival staining, and Schirmer test.

TBUT was measured (in seconds) 3 times in each eye during the 2 minutewait for corneal staining. Fluorescein supplied for the study wasapplied onto the superior bulbar conjunctiva. This 1 instillation ofsodium fluorescein was used for TBUT and corneal staining. However, ifneeded, the fluorescein could have been reapplied for the cornealstaining after the TBUT. The examination was performed with the slitlamp at 10×magnification using cobalt blue illumination and the yellowbarrier filter. Three consecutive TBUTs were performed in each eye andall 3 measurements were timed with the stopwatch provided.

The Schirmer Test (with Anesthesia) was performed in each eye after allother ophthalmic testing. One drop of anesthetic was instilled and thetest begun precisely 4 minutes after instillation. The test wasconducted in a dimly lit room. While the subject looked upward, thelower lid was gently drawn downward and temporally. The rounded bent endof the sterile strip was hooked in the lower conjunctival sac over thejunction of the temporal and central one-third of the lower eyelidmargin in each eye. After 5 minutes, the tear front was marked andmeasured on each of the sterile strips.

The raw values of these measures were summarized for the ITT population,with missing data imputation using LOCF at each scheduled follow-upvisit. The treatment difference and 95% CI for between-treatmentcomparisons were calculated. The treatment differences and 95% CIs inchange from baseline in OSDI score at day 30 between Formulation B andFormulation A, Formulation A and OPTIVE MD were also analyzed assecondary efficacy variables.

The Formulation B group was noninferior to the OPTIVE UD and FormulationA groups in the secondary efficacy measures of TBUT, corneal staining,conjunctival staining, and Schirmer test.

Efficacy Conclusions:

The objective of the current study was to evaluate the safety, efficacyand acceptability of the Formulation B in subjects with signs andsymptoms of dry eye disease. The study was performed to compare theFormulation B to existing OPTIVE UD formulation and also to theFormulation A. The primary efficacy endpoint was met in this study.

There was no difference between the Formulation B group and the controlOPTIVE UD group in the mean change from baseline in OSDI score at day30. The Formulation B formulation was noninferior to OPTIVE UD andFormulation A in reducing the severity of symptoms of dryness asmeasured by the OSDI questionnaire. Although there were statisticallysignificant differences between the Formulation B and Formulation Agroup in the overall analyses and subgroup analyses (by OSDI stratum) ofthe primary efficacy measure, favoring the Formulation B group, thestudy was not designed to test statistical superiority between the twogroups, therefore firm conclusions regarding the superiority ofFormulation B versus Formulation A cannot be made. Since this was a4-arm study, efficacy comparisons between the Formulation A and OPTIVEMD formulations were also performed. Overall there was no difference inefficacy between the Formulation A and OPTIVE MD formulations.

The Formulation B formulation appeared to have an acceptable safetyprofile.

Efficacy: The results of this study demonstrate that the Formulation Bformulation is noninferior to the OPTIVE UD formulation in reducing theseverity of symptoms of dryness in subjects with mild to severe dry eye.

In a different study, it has been shown that Formulation B reducesevaporation of tears, helping therefore the tear film stability andprotecting the tear film osmotic balance in case a hyperosmotic shiftshould occur. Formulation B reduced evaporation in subjects with andwithout dry eye syndrome.

The following non-limiting examples illustrate further certain aspectsof the present invention:

EXAMPLE 3

Eye drops of Formulation B, are administered to the eye of a patient,Caucasian 52 year old male, complaining about dry eyes. After applyingthe eye drops twice daily in each eye for two days the patient hasrelief from dry eye symptoms.

EXAMPLE 4

A drop of Formulation A is administered to the each eye of a personsuffering from dry eye, one to three times a day. After two days theperson feels relief from the dry eye symptoms.

It is to be understood that the embodiments disclosed herein areillustrative of the principles of the claims. Other modifications thatmay be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

What is claimed is:
 1. An ophthalmic composition comprisingpolyoxyethylene (80) sorbitan monooleate, carboxymethylcellulose sodium,glycerin, boric acid, acrylates/C10-30 alkyl acrylate crosspolymer,castor oil, erythritol, levocarnitine, sodium hydroxide, and water. 2.The composition of claim 1, wherein the polyoxyethylene (80) sorbitanmonooleate is present at a concentration of about 0.1% w/w to about 2%w/w.
 3. The composition of claim 1 wherein the carboxymethylcellulosesodium is present at a concentration of about 0.1 w/w to about 2% w/w.4. The composition of claim 1, wherein the glycerin is present at aconcentration of about 0.2% w/w to about 5% w/w.
 5. The composition ofclaim 1, wherein the boric acid is present at a concentration of about0.02% to about 2% w/w.
 6. The composition of claim 1, wherein theacrylates/C10-30 alkyl acrylate crosspolymer is present at aconcentration of about 0.02% to about 0.5% w/w.
 7. The composition ofclaim 1, wherein the castor oil is present at a concentration of about0.05% to about 0.5% w/w.
 8. The composition of claim 1, wherein theerythritol is present at a concentration of about 0.05% or about 3% w/w.9. The composition of claim 1, wherein the levocarnitine is present at aconcentration of about 0.05% or about 3% w/w.
 10. The composition ofclaim 1, wherein the pH is about 7.3.
 11. The composition of claim 1,comprising about 0.5% w/w polyoxyethylene (80) sorbitan monooleate,about 0.5% w/w carboxymethylcellulose sodium, about 1.0% w/w glycerin,about 0.6% w/w boric acid, about 0.1% w/w acrylates/C10-30 alkylacrylate crosspolymer, about 0.25% w/w castor oil, about 0.25% w/werythritol, about 0.25% w/w levocarnitine, sodium hydroxide, a pH ofabout 7.3 and water.
 12. A method of treating, diagnosing, curing,mitigating or preventing dry eye syndrome comprising administering aneffective amount of an ophthalmic composition according to claim 1 to aneye of a man or other animal in need thereof.
 13. The method accordingto claim 12, wherein the ophthalmic composition comprises about 0.5% w/wpolyoxyethylene (80) sorbitan monooleate, about 0.5% w/wcarboxymethylcellulose sodium, about 1.0% w/w glycerin, about 0.6% w/wboric acid, about 0.1% w/w acrylates/C10-30 alkyl acrylate crosspolymer,about 0.25% w/w castor oil, about 0.25% w/w erythritol, about 0.25% w/wlevocarnitine, sodium hydroxide, a pH of about 7.3 and water.
 14. Thecomposition of claim 1, further comprising stabilized oxychlorocomplexes.
 15. The composition of claim 14, wherein the stabilizedoxychloro complexe is present at a concentration of about 0.002% orabout 0.05% w/w.
 16. The ophthalmic composition of claim 11, furthercomprising about 0.01% w/w of stabilized oxychloro complexes.
 17. Amethod of treating, diagnosing, curing, mitigating or preventing dry eyesyndrome comprising administering an effective amount of an opthalmiccomposition according to claim 14 to an eye of a man or other animal inneed thereof.
 18. The method according to claim 17, wherein theophthalmic composition comprises about 0.5% w/w polyoxyethylene (80)sorbitan monooleate, about 0.5% w/w carboxymethylcellulose sodium, about1.0% w/w glycerin, about 0.01% w/w of stabilized oxychloro complexes,about 0.6% w/w boric acid, about 0.1 w/w acrylates/C10-30 alkyl acrylatecrosspolymer, about 0.25% w/w Castor Oil, about 0.25% w/w erythritol,about 0.25% w/w levocarnitine, sodium hydroxide to obtain a pH of about7.3 and water.